Cleft lip and palate are among the most common birth defects, which are mainly due to genetic causes. It is not yet known exactly which genes are affected. A study conducted by the University of Bonn has now discovered new correlations: new mutations near known genes such as SPRY1 could contribute to increased disease risk. There is also evidence that the Musculin transcription factor is causally involved. The results have now been published online in advance in the journal Human genetics and advances in genomics. The final version will follow soon.
In cleft lip and palate, the formation of the buccal region is altered during embryonic development. To date, more than 45 gene segments are known to contain common risk variants. “We have now also found an enrichment of rare variants, in particular new mutations, in two of these regions,” explains Dr. Kerstin U. Ludwig, leader of an Emmy Noether group at the Institute of Human Genetics at the Bonn University Hospital.
The researchers further used novel data analysis methods to find evidence that the transcription factor Musculin also plays a role. “This suggests an involvement of embryonic development of facial muscles in cleft lip and palate,” says lead author Hanna Zieger, a member of Ludwig’s team. “It had already been suspected, but not yet demonstrated.”
Many genetic studies focus primarily on the regions of the genome that contain the code for making proteins. “We combined different approaches to interpret rare variants in the 98% that do not directly code for proteins,” Ludwig reports. One of these approaches examines the regions of the genome to which transcription factors can bind. These are proteins that recognize specific DNA base sequences, bind to them and thus influence the reading of neighboring genes. One such transcription factor is Musculin.
Using his specially adapted evaluation methods, Zieger was able to show that the base sequence of the Musculin binding sites is altered more often and to a greater extent in patients than in the control group. “The assessment script written by Ms. Zieger can also be used for other diseases,” says Ludwig, who is a member of the ImmunoSensation2 cluster of excellence.
Like a needle in a haystack
The team used publicly available genome sequencing data from the Gabriella Miller Kids First program of more than 200 children with cleft lip and palate and their parents. In collaboration with the Berlin Institute of Health and the Max Delbrück Center for Molecular Medicine (Berlin), the researchers filtered out genetic variants that occur only in affected children but not in their parents. More than 13,000 of these “new mutations” have been collected in this way. The researchers compared them to about 17,000 new mutations from unconditional families.
The goal now was to identify these novel mutations in patients with cleft lip and palate that were significantly more common in patients than in control subjects. “In this way, we were able to identify a section on chromosome 4. This section is close to the SPRY1 gene, which was already known to be a cleft lip and palate gene due to common variants,” summarizes Ludwig.
The head of the research group highlights the achievements of Hanna Zieger, who carried out the study as lead author during her MD, largely during the coronavirus pandemic: “She learned the basics of data analysis at lightning speed and has programmed or adapted many analytical tools.” Hanna Zieger is currently completing part of her practical year in Dresden before obtaining her third state examination in medicine in the spring. She also plans to pursue research after graduation.
The results of this study provide new insights into the biological mechanisms that contribute to cleft lip and palate. Next, the research team plans to further evaluate the Gabriella Miller Kids First program dataset and use additional patient groups to further clarify if and how other transcription factors are also involved. in cleft lip and palate and how the risk variants interact with each other. .
Participating Institutions and Funding:
In addition to the Institute of Human Genetics, the study involved the Institute of Medical Biometrics, Informatics and Epidemiology, the Department of Oncology of Medical Clinic III and the Institute of Genomic Statistics and Bioinformatics of the University Hospital Bonn, as well as the Berlin Institute of Health and Max Delbrück Center for Molecular Medicine (Berlin). The BONFOR program of the Faculty of Medicine of the University of Bonn and the German Research Foundation funded the study.
Publication: Hanna K. Zieger, Leonie Weinhold, Axel Schmidt, Manuel Holtgrewe, Stefan A. Juranek, Anna Siewert, Annika B. Scheer, Frederic Thieme, Elisabeth Mangold, Nina Ishorst, Fabian U. Brand, Julia Welzenbach, Dieter Beule, Katrin Paeschke, Peter M. Krawitz, Kerstin U. Ludwig: Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations, Human Genetics and Genomics Advances, DOI: https: //doi.org/10.1016/j.xhgg.2022.100166
Dr AS Kerstin U. Ludwig
Emmy Noether group leader
Institute of Human Genetics
Bonn University Hospital
Such. +49 (0)228 6885420
Advances in human genetics and genomics
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Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations
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